One hundred eighty-four patients with hepatitis B surface antigen-positive chronic hepatitis were evaluated for antibodies to hepatitis C virus (anti-HCV). Only 11 (8%) of 136 patients with hepatitis B virus (HBV) replication (HBV-DNA-positive in serum) while 7 (35%) of 20 positive for antibody to hepatitis B e antigen (anti-HBe) but HBV-DNA-negative were positive for anti-HCV. By contrast, anti-HCV was never found in 30 anti-HBe-positive "healthy" carriers. Anti-HCV was more frequent in hepatitis D virus (HDV)-positive than in HDV-negative cases (32% vs. 12%). During 1-11 years of follow-up, anti-HCV persisted in 90% of cases, who showed continuing alanine aminotransferase elevation. Liver histology deteriorated in 2 of 4 anti-HCV-positive, anti-HBe-positive, HBV-DNA-negative patients. These results demonstrate the existence of a subgroup of patients with anti-HBe-positive, HBV-DNA-negative, HDV-negative chronic hepatitis B, where HCV may play a leading role in causing liver disease.